Ketamine flow synthesis

ABSTRACT

The invention provides a method for synthesizing a compound of formulawherein each R independently represents an optionally substituted aryl, heteroaryl, alkyl, perfluoroalkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, cyano, sulfo or sulfhydryl group, in ortho, meta or para position to the cycloalkylamine moiety; R1 and R2 each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group; R3 represents a hydrogen group, substituted aryl, heteroaryl, alkyl, perfluoroalkyl, cycloalkyl, alkoxy, aryloxy group; Y represents an oxygen atom, a sulfur atom, a NH group, a NR4 group or a CH2 group;R4 represents a hydrogen atom or an alkyl, aryl or a heteroaryl group; and n and m each independently represents an integer from 1 to 5; or a pharmaceutically acceptable salt thereof; or a precursor thereof; wherein the method comprises one or more of the following steps: (a) reacting a compound of formula (II)wherein R, R3, Y, n and m are as defined above in relation to the compound of formula (I) with an oxygenating agent, a first additive and a second additive in a solvent in a fluidic network or in a batch process under thermal and/or photochemical conditions to form a compound of formula (III):wherein R, R3, Y, n and m are as defined above in relation to the compound of formula (I), (b) reacting a compound of formula (III) with a nitrogen containing nucleophile in the presence of a third additive and/or a solvent in the fluidic network or in a batch process under thermal conditions to form a compound of formula (IV):wherein R, R1, R2, R3, Y, n and m are as defined above in relation to the compound of formula (I); and/or(c) reacting a compound of formula (IV) in a fluidic network or in a batch process, optionally in the presence of a fourth additive, under thermal conditions to form a compound of formula (I); wherein one or more of steps (a), (b) and/or (c) is carried out in a fluidic network that comprises micro- and/or meso-channels having an internal dimension of from 100 μm to 2000 μm.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/896,909, filed Jun. 9, 2020, which is a bypass continuation ofInternational Application No. PCT/EP2018/097033, filed Dec. 27, 2018 andpublished as WO/2019/129815 on Jul. 4, 2019, in English, which claimspriority to European patent application Serial No. EP17211200.5, filedDec. 29, 2017, the contents of which are hereby incorporated byreference in their entirety.

The present invention relates to an improved process for theatom-economic preparation of libraries of significantarylcycloalkylamine derivatives, or intermediates thereof.

Significant arylcycloalkylamine derivatives include phenylcyclidine 0and ketamine rac-1.

Arylcyclohexylamine derivatives are a class of importantpharmaceutically active ingredients. A typical arylcyclohexylaminederivative bears a cyclohexylamine backbone featuring an aryl moietyattachment. Important characteristics of arylcyclohexylamine derivativesare (a) that the aryl moiety is in geminal position to the amine; (b)the amine is typically secondary or tertiary.

Phencyclidine is one of the first arylcyclohexylamine that was reportedwith recognized anesthetic properties, as well as dissociativehallucinogenic and euphoriant effects.

Ketamine belongs to the arylcyclohexylamine pharmaceutical class, andwas first accepted as an ingredient for anesthetic cocktails in the late1960s on humans and for veterinary use. Because of strong dissociativeside effects, it has become a Schedule III, non-narcotic substance underthe Controlled Substances Act since 1999.

Ketamine is now considered as a breakthrough medication for treatingmajor depressive disorders with imminent risk for suicide, and is listedon the World Health Organization (WHO) list of essential medicines.According to WHO, depression will become the second cause of disabilityby 2020, after cardiovascular diseases. Today, the global burden ofdepression is a major public health challenge, both at the social andeconomic levels. Despite the availability of various antidepressants,several weeks, if not months, are necessary to be effective on patients.Ketamine, on the contrary, is effective after the first intake (M. W.Tyler et al., ACS Chem. Neurosci. 2017, 8, 1122).

Ketamine, (also known as2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) bears one stereogeniccenter that accounts for 2 enantiomers, namely,(S)-2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone (a.k.a. Esketamine,referred to herein as the compound of formula 1a) and(R)-2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone (a.k.a. Arketamine,referred to herein as the compound of formula 1b).

The most active enantiomer of ketamine is 1a, although there is stillmuch debate regarding the intimate mechanism of action leading to itsantidepressant activity. The pharmacology profile of ketamine is complexand not completely resolved yet. According to Tyler et al., ketamineacts on the central nervous system (CNS). It is a non-competitiveglutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist withmoderate potency. The (S)-enantiomer 1a is more potent (IC₅₀: 465 nM)than the (R)-enantiomer 1b (IC₅₀: 1.340 nM).

The most common pharmaceutical formulation of ketamine consists of anaqueous solution of the racemate as a hydrochloride salt (Ketalar,Calypsol, Vetalar). Eskatemine 1 a is also sold as an aqueous solutionof its hydrochloride under the brand name Ketanest.

Ketamine is exclusively produced in batch, according to stepwise,time-consuming processes that use environmentally harmful/unsafeconditions or reagents.

A variety of methods have been reported in the art for the preparationof ketamine. Some of these methods afforded the racemate. “Racemate”refers to a 50:50 mixture of enantiomer 1a and 1b, withoutdiscrimination. For instance, the original procedure reported in theearly 1960s by C. L. Stevens (U.S. Pat. No. 3,254,124), involves 4different steps that are typically run sequentially, in temporally andspatially disconnected macroscopic batch reactors. This sequence ofreactions is particularly long (over 7 days from advanced startingmaterial 2), and prone to many side reactions (Scheme 1). Step 1involves the bromation of intermediate 2, typically withN-bromosuccinimide or bromine, benozyl peroxide and carbontetrachloride. Although alternative methods using copper salts werereported, (Gant, T. G. U.S. Pat. No. 7,638,651 B2) this step generates aconsiderable amount of waste, and the resulting bromoketone 3 isreported as instable. Bromoketone 3 is next reacted with puremethylamine at room temperature leading to hydroxyimine 4a. The latterstep is time consuming (5 days), and comes with major impurities thatrequire extensive purification. One of the main impurities (4b)corresponds to formula (2), and it affects drastically the purity of 1.Step 3 involves the thermolysis of 4a toward the formation of rac-1 inrefluxing decalin (b.p. 186° C.) or in refluxing dichlorobenzene (b.p.180° C.) for 2 h. Step 4 aims at the formation of the hydrochloric saltrac-1-HCl. Steps 3 and 4 can be combined (step 3′) upon thermolysis of4a in the presence of an acid, such as HCl. Steps 2 and 3 lead tosignificant impurities. Step 3 is very sensitive to reaction time andtemperature. The presence of impurity 4b negatively affects thethermolysis step.

More recently, a copper-assisted method utilizing ammonium nitrate forthe direct nitration of cyclic ketones was reported by Zhang Z. Q et alin Org. Lett 2017, 19 (5), 1124-1127. The method was also applied forthe preparation of racemic ketamine (rac-1), with an overall isolatedyield of 25% (3 steps).

Other methods were dedicated to the enantioselective preparation of 1aor 1b. Some methods use expensive metal catalysts or organocatalystscombined with time-consuming multistep sequences, affording ketaminewith combined yields ranging from 21 to 30% overall and enantiomericexcesses of up to 99%. For instance, Yokoyama et al. (Tetrahedron 2009,65 (27), 5181-5191) reported in 2009 an asymmetric synthesis ofesketamine 1a according to 10 steps in 21% overall yield (99% ee). In2015, Toste et al. (J. Am. Chem. Soc. 2015, 137 (9), 3205-3208) reporteda procedure for the direct asymmetric amination of α-substituted ketoneswith di-tert-butyl azodicarboxylates catalyzed by a chiralorganophosphoric acid. Esketamine 1a was obtained accordingly in 30%overall yield (99% ee).

These methods reported in the art come with shortcomings associated withpoor global efficiency (low yield) and poor atom-economy (lots ofwaste). Some of these methods use unstable chemical intermediates, whichare prone to decomposition or give rise to side reactions, henceimpacting the final purity. These methods also come with shortcomingsassociated to trace contamination of the final product with toxicmetals. These methods use environmental unfriendly conditions, noxiousreagents and solvents. These methods use stepwise macroscopic batchprocesses, which come with various shortcomings inherent to thetechnology, such as poor mixing and heat transfer, which ultimatelyaccount for low productivity, quality deficiency and poor flexibility. Ahigh chemical risk is associated with classical large scale, stepwisebatch processes, in particular for multistep sequences involving hightemperatures and/or strong oxidizers in conjunction with flammableorganic solvents. Batch reactors also come with internal temperaturegradients that are deleterious for chemical processes using sensitivesubstrates. Poor thermal control on such processes leads to low purityprofiles, hence increasing process costs with extensive purifications.

A way of ameliorating these problems has been sought.

According to the invention there is provided a method for synthesizing acompound of formula

wherein each R independently represents an optionally substituted aryl,heteroaryl, alkyl, perfluoroalkyl, cycloalkyl, alkoxy, aryloxy, acyl,carboxyl, hydroxyl, halogen, amino, nitro, cyano, sulfo or sulfhydrylgroup, in ortho, meta or para position to the cycloalkylamine moiety;R¹, R², and R³ each independently represent a hydrogen atom, a loweralkyl group or a cycloalkyl group;Y represents an oxygen atom, a sulfur atom, a NH group, a NR⁴ group or aCH₂ group;R⁴ represents a hydrogen atom or an alkyl, aryl or a heteroaryl group;andn and m each independently represent an integer from 1 to 5; andor a pharmaceutically acceptable salt thereof; or a precursor thereof;wherein the method comprises one or more of the following steps:(a) reacting a compound of formula (II)

wherein R, R³, Y, n and m are as defined above in relation to thecompound of formula (I) with an oxygenating agent, a first additive, anda second additive in a solvent in a fluidic network or in a batchprocess under thermal and/or photochemical conditions to form a compoundof formula (III):

wherein R, R³, Y, n and m are as defined above in relation to thecompound of formula (I), (b) reacting a compound of formula (III) with anitrogen containing nucleophile in the presence of a third additiveand/or a solvent in the fluidic network or in a batch process underthermal conditions to form a compound of formula (IV):

wherein R, R₁, R₂, R₃, Y, n and m are as defined above in relation tothe compound of formula (I); and/or(c) reacting a compound of formula (IV) in a fluidic network or in abatch process, optionally in the presence of a fourth additive, underthermal conditions to form a compound of formula (I); wherein one ormore of steps (a), (b) and/or (c) is carried out in a fluidic networkthat comprises one or more micro- and/or meso-channels having aninternal dimension of from 100 μm to 2000 μm.

The present invention significantly reduces the impurity profile, theenvironmental footprint and the costs associated with conventionalprocesses toward significant arylcycloalkylamine derivatives.

A significant arylcycloalkylamine derivative is ketamine rac-1, which isdefined a compound of formula I wherein R represents a chlorine atom inortho position to the cycloalkyl moiety, R¹ represents a methyl group,R² represents a hydrogen atom, R³ represents a hydrogen atom, Yrepresents a CH₂ group, n represents 1, and m represents 2, and thecompound is pharmaceutically formulated as a hydrochloride salt.

Advantages of performing one or more of steps (a), (b), and/or (c) in afluidic network include:

-   -   a low environmental footprint, and uses environment-friendly        conditions;    -   production of significant arylcycloalkylamine derivatives        related to ketamine in high overall yields and excellent purity;    -   accurate control on the reaction conditions, such as a control        of the temperature, the pressure, the irradiation time, the flow        rate and the local stoichiometry;    -   allows to quickly expose chemicals to high reaction temperatures        without the formation of deleterious temperature gradients:    -   permits to obtain a product with a constant quality and purity        profile;    -   enables a substantially safer handling of an oxygenating agent        in the presence of flammable organic solvents at high        temperature;    -   provides a scalable, safe and intensified continuous-flow        process towards an arylcycloalkylamine derivatives related to        ketamine or a prodrug or a derivative or an intermediate thereof        with high atom-economy and high efficiency;    -   enables short reaction times    -   the fluidic network setup may use intensified thermal conditions        to accelerate the chemical processes and reactions, and at least        one critical step can be alternatively performed under        photochemical conditions;    -   by streamlining multiple operations within the same        uninterrupted fluidic reactor network comprising        micro-/meso-channels, the present invention thus alleviates the        handling of any of the chemical intermediates and large        inventories of chemical intermediates;    -   the process is amenable to the production of libraries of        ketamine analogs using diverse arylcycloalkylamine precursors        with various aromatic substitution, diverse (hetero)cycloalkyl        fragments and various amines;    -   the process further enables a productivity that can be adapted        depending on the demand. Each step of the process can be run        independently or conjointly in the continuous-flow        micro-/meso-reactor network.

In some embodiments, one or more of the steps of the method may compriseone or more of the following steps: (i) flowing a fluid sample into amicro-/meso-channel; and/or (ii) performing an in-line purification;and/or (iii) performing an in-line analysis; and/or (iv) performing achemical reaction in the micro-/meso-channel. It should be understoodherein that a micro- and/or meso-channel is a channel which has aninternal dimension of from 100 μm to 2000 μm, in which chemicals can bemixed, heated or cooled, or reacted. In some embodiments, the micro-and/or meso-channel may be of circular section such as a cylinder or atube. In some embodiments, the micro- and/or meso-channel may integratevarious elements such as static mixers.

Some steps of this method can be performed in batch to produce chemicalintermediates which can next be transformed under continuous-flowconditions, such as for process steps involving high temperature orconditions that would typically be considered unsafe under batchconditions by one skilled in the art.

In some embodiments, step (a) of the method comprises reacting acompound of formula (II) with an oxygenating compound, a first additivewhich is a reductant and a second additive which is a base in a solventin the fluidic network under thermal conditions to a compound of formula(III). In some embodiments, step (a) of the method comprises reacting acompound of formula (II) with an oxygenating compound, a first additivewhich is a reductant and a second additive which is a base for areaction time of about 60 min or less, to produce a compound of formula(III). In some embodiments, the second additive which may be a baseoptionally containing a co-reagent for enhancing the performance of thereaction. In some embodiments, a co-reagent may be a reagent that isadded to the system in order to cause a chemical reaction or to enhanceperformance of a reaction while not necessarily being consumed in thesaid reaction. It should be understood herein that enhancing theperformance of the reaction means to increase the conversion and/or theselectivity. Whether the co-reagent needs to be included in the reactionmixture depends on the nature of the base. In some embodiments, step (a)of the method may comprise reacting a compound of formula (II) with anoxygenating compound, a first additive which is a reductant and a secondadditive which is a base in a substoichiometric amount in a solvent fora reaction time of about 60 min or less at a temperature of 150° C. orless, to produce a compound of formula (III). It should be understoodherein that substoichiometric mean that the base is added in less thanthe equimolar amount (=100 mol %), for example 50% mol or less. In someembodiments, where the base is used in a substoichiometric amount, theoptional co-reagent may be used with the same molar ratio (e.g. 50 mol %base, 50 mol % co-reagent). In some embodiments, step (a) of the methodmay comprise reacting a compound of formula (II) with an oxygenatingcompound with a first additive which is a reductant and a secondadditive which is a base in a catalytic amount in a solvent for areaction time of about 60 min or less at a temperature of 150° C. orless, to produce a compound of formula (III). It should be understoodherein that catalytic means that this base is added in an amount lessthan 10 mol %. In some embodiments, where the base is used in acatalytic amount, the optional co-reagent may be used with the samemolar ratio (e.g. 5 mol % base, 5 mol % co-reagent). In someembodiments, the first additive which is a reductant can be added afterthe reaction of compound of formula (II) with an oxygenating compound inthe presence of a second additive which is a base. In some embodiments,a fluidic network comprising micro- and/or meso-channels is utilized instep (a) of the method. Herein a micro-channel means a channel with aninternal dimension of from 100 μm to 850 μm; micro-fluidic reactor meansa reactor which comprises a network of micro-channels and variousfluidic elements assembled in modules; meso-channel means a channel withan internal dimension of from 850 μm to 2000 μm; meso-fluidic reactormeans a reactor which comprises a network of meso-channels and variousfluidic elements assembled in modules. Reaction time may alternativelybe expressed as a residence time in the fluidic network. Residence timemeans the actual process time under the specific process conditions(temperature, pressure, irradiation) inside the controlled environmentof a micro-/meso-fluidic reactor and is generally expressed in minutes.The residence time may be calculated from the ratio of the internalvolume of a fluidic reactor and the total flow rate in the fluidicreactor.

In some embodiments, step (a) of the method comprises reacting acompound of formula (II) with an oxygenating compound, and a firstadditive which is a reductant and second additive which contains a baseand a catalyst in a solvent in the fluidic network under photochemicalconditions to a compound of formula (III). In some embodiments, step (a)of the method comprises reacting a compound of formula (II) with anoxygenating compound, a first additive which is a reductant and a secondadditive which contains a base and a catalyst in a solvent for areaction time of about 60 min or less, to produce a compound of formula(III).

In some embodiments, step (a) of the method comprises using a fluidicnetwork comprising transparent micro- and/or meso-channels. Herein, atransparent micro- and/or meso-channel is a micro- and/or meso-channelconstructed from a material that is fully transparent to light. In someembodiments, the material of micro- and/or meso-channel is transparentto light with wavelengths ranging from 300 to 800 nm, but morespecifically from 400 to 600 nm. In some embodiments, a transparentmicro- and/or meso channel may be constructed from glass, fused silica,and/or a transparent polymer.

In some embodiments, step (a) can be telescoped to subsequent processoperations, such as to step (b). In some embodiments, step (a) can betelescoped to a subsequent process operation such that step (a)additionally comprises a step of an in- or off-line downstreampurification including quench, liquid-liquid extraction, liquid-liquidseparation, gas-liquid separation, filtration on silica gel or in-linecrystallization. In some embodiments, liquid-liquid extraction requiresthe injection of a secondary phase, such as an additional reagent in asolvent. In some embodiments, in-line liquid-liquid or gas-liquidseparation involves a membrane or a settling tank. In some embodiments,the liquid-liquid separation and the gas-liquid separation are effectedat the same time. Herein, telescoping means the integration of multipleprocess or chemical operations within the same uninterrupted fluidicreactor network. In some embodiments, one or more steps of the method ofthe invention comprises in-line analysis including but not restricted toin-line IR monitoring or other spectroscopic methods for processmonitoring purposes.

In some embodiments, step (b) comprises an imination reaction. In someembodiments, step (b) may have a yield of more than 50%. In someembodiments, step (b) may have a yield of more than 90% within areaction time of less than 10 min, and typically less than 2 min at areaction temperature of less than 150° C., such as less than 100° C. ormore specifically 60° C. In some embodiments, step (b) uses a fluidicnetwork comprising micro- and/or meso-channels. In some embodiments,step (b) comprises use of a third additive which is a dehydrationreactant. In some embodiments, a dehydrating reactant may be adehydrating solvent. In some embodiments, step (b) is performed in adehydrating solvent. An example of dehydrating reactant is a co-reactantsuch as triethylorthoformate, sulfuric acid, or a trialkyl borate suchas triethyl or triisopropyl borate and/or a solvent such as absoluteethanol (or anhydrous ethanol).

In some embodiments, step (b) can be telescoped to subsequent processoperations, such as to step (c). In some embodiments, step (b) may betelescoped to a subsequent process operation such that step (b)additionally comprises a step of an in- or off-line downstreampurification including quench, liquid-liquid extraction, liquid-liquidseparation, or gas-liquid separation. In some embodiments, in-lineliquid-liquid or gas-liquid separation involves a membrane or a settlingtank. In some embodiments, the liquid-liquid separation and thegas-liquid separation are effected at the same time.

In some embodiments, step (b) of the method is performed for a reactiontime of about 60 min or less. Reaction time may alternatively beexpressed as a residence time in the fluidic network.

In some embodiments, step (b) can be telescoped to subsequent chemicaloperations, including chemical reactions, such as step (c). In someembodiments, the method comprises a continuous-flow method forsynthesizing a compound of formula (I). In some embodiments, the methodof the invention includes flowing a fluid sample comprising a compoundof formula (IV) into a micro-/meso-channel; and/or performing an in-linepurification of the compound of formula (IV); and/or performing anin-line analysis of the compound of formula (IV); and/or performing achemical reaction, in the micro-/meso-channel, to convert the compoundof formula (IV) to the compound of formula (I).

In some embodiments, step (c) comprises a thermal rearrangementreaction. It should be understood herein that a thermal rearrangementmeans that step (c) includes heating a compound of formula (IV) at atemperature above room temperature in a solvent. In some embodiments,the thermal rearrangement may use heating at a temperature above 100°C., and more specifically above 150° C. In some embodiments, step (c)may have a yield of more than 50%. In some embodiments, step (c) mayhave a yield of more than 80% within a reaction time of less than 30min, and typically less than 15 min. In some embodiments, step (c) usesa fluidic network comprising micro- and/or meso-channels. In someembodiments, step (c) requires a fourth additive such as a homogeneousBrønsted or a Lewis acid. In some embodiments, step (c) may comprise anadditive such as a heterogeneous Brønsted or Lewis acid. In someembodiments, the fourth additive combines both heterogeneous Brønstedand Lewis acidic sites such as, but not restricted to, MontmorilloniteK10 or other clays. In some embodiments, step (c) is performed in thesame solvent as for steps (a) and/or (b). In some embodiments, theproducts or effluents of steps (a) and (b) can be utilized directly forperforming step (c), that is, without intermediate purification. In someembodiments, step (c) may be performed in an aprotic non-polar solventsuch as toluene or decalin. In some embodiments, the effluent of step(c) may be collected in a batch surge containing a pharmaceuticallyacceptable acid.

In some embodiments, a fluidic network comprising micro- and/ormeso-channels may be utilized in step (c) of the method. In someembodiments, a fixed bed reactor may be utilized in step (c). it shouldbe understood herein that a fixed-bed reactor is a column with a muchlarger diameter than a conventional fluidic reactor (>2000 μm) that ispacked with a solid catalyst. In some embodiments, the fixed-bed reactormay be packed with Montmorillonite K10 and/or another clay. In someembodiments, the fourth additive may have a specific granulometry. Itshould be understood herein that granulometry is the measurement of thesize distribution in a collection of particles. In some embodiments, thefourth additive may have a specific granulometry of 0.5-1.25 mm. In someembodiments, the fourth additive may have a specific granulometry of<0.5 mm.

In some embodiments, step (c) can be telescoped to subsequent processoperations, such that step (c) additionally comprises a step of an in-or off-line downstream purification including quench, liquid-liquidextraction, liquid-liquid separation, gas-liquid separation, filtrationon silica gel, in- or off-line crystallization.

In some embodiments, step (c) can be telescoped to subsequent chemicaltransformations including:

(i) reaction of a compound of formula (I) with a pharmaceuticallyacceptable acid to form a pharmaceutically acceptable salt of a compoundof formula (I), or an analog thereof; and/or

(ii) a reaction of a compound of formula (I) with an organic and/orinorganic base or acid to increase the amount of a specific stereoisomerof the compound of formula (I), such as Esketamine (1a).

In some embodiments, step (c) of the method is performed for a reactiontime of about 60 min or less. Reaction time may alternatively beexpressed as a residence time in the fluidic network. In someembodiments, step (c) (i) of the method is performed for a reaction timeof about 30 min or less. In some embodiments, steps (c) (ii) of themethod of the invention are performed for a reaction time of about 60min or less. Reaction time may alternatively be expressed as a residencetime in the fluidic network.

In some embodiments, step (b) and (c) of the method are combined andperformed simultaneously for a reaction time of about 60 min or less inthe same fluidic network comprising micro- and/or meso-channels.

In some embodiments, step (c) can be telescoped to subsequent processoperations. In some embodiments, step (c) additionally comprises a stepof an injection of a solution comprising a pharmaceutically acceptableacid to react with a free base of formula (I), such that a salt of thesaid acid and the compound of formula (I) is formed. In someembodiments, step (c) additionally comprises a step of an injection ofantisolvent in a section of fluidic network comprising a micro- and/ormeso-channel to crystallize a pharmaceutically acceptable acid to form asalt of a compound of formula (I), or an analog thereof. Herein, itshould be understood that an antisolvent is a solvent in which a salt ofa compound of formula (I) is less soluble. A solvent/antisolvent mixtureis a component for obtaining crystals. In some embodiments, the effluentof step (c) is collected in a batch surge, and the antisolvent is addedafterwards. In some embodiments. (c) can be telescoped to a step thatcomprises flowing a salt of a compound of formula (I) in a section offluidic network comprising a micro- and/or meso-channel in which thetemperature is decreased from an initial value to a target lowertemperature. In some embodiments, the initial value is the processtemperature of step (c), and the target lower temperature is from 100°C. to −25° C., for example from 50° C. to 5° C. The purpose of theprocess of decreasing the temperature is to create a supersaturation,and is known by one skilled in the art as cooling crystallization. Insome embodiments, the effluent of step (c) is collected in a batchsurge, and the cooling crystallization is performed afterwards.

In some embodiments, in step (c) the solvent used is an alcohol in whichthe solubility of a pharmaceutically acceptable salt of a compound offormula (I) can be altered either by cooling or by adding anantisolvent. In some embodiment the pharmaceutically acceptable salt ofa compound of formula (I) is a hydrochloride salt. In some embodiments,the antisolvent is an ether (such as a dialkyl ether) or an oxygenousheterocycle (such as, but not restricted to, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane), or an alkane (such as, but notrestricted to, hexane or heptane), or a cycloalkane (such as, but notrestricted, cyclohexane). In some embodiments, the ratio by volume ofantisolvent to solvent may range from 1:1 to 1:10, for example from 1:1to 1:3.

In some embodiments, the method of invention may be performed using afully telescoped system. A fully telescoped system comprises a series ofmicro- and/or meso-reactors which perform the steps of the method of theinvention in sequence, without any interruption or isolation or handlingof an intermediate compound. Advantages of using a fully telescopedsystem include that it can give:

-   -   a compound of formula (I) as a free base in at least 50%        isolated yield (99% conversion of the compound of formula (II)).        (It should be understood that a free base is a        nitrogen-containing molecule where the nitrogen atom has not        reacted with a pharmaceutically acceptable acid.);    -   a racemic ketamine of formula 1a+1b as a free base in at least        50% isolated yield (99% conversion of the compound of formula        (II);    -   a pharmaceutically acceptable salt in at least 50% isolated        yield (99% conversion of the starting arylcycloalkylamine        precursor of formula (II) (a typical example of a        pharmaceutically acceptable salt is as a hydrochloride salt);        and    -   a racemic ketamine of formula 1a+1b as a pharmaceutically        acceptable salt in at least 50% isolated yield (99% conversion        of the starting arylcycloalkylamine precursor of formula (II) (a        typical example of a pharmaceutically acceptable salt is as a        hydrochloride salt).

The compound of formula (II) which is the starting material of themethod of the invention is available following an adapted procedure fromthe art, such as the one disclosed in U.S. Pat. No. 7,638,651 B2. Insome embodiments, the compound of formula (II) may be prepared under acontinuous-flow strategy using a flow reactor comprising micro- and/ormeso-fluidic modules. In some embodiments, the compound of formula (II)may be obtained under continuous-flow conditions by adapting the knownbatch procedures. In some embodiments, the conditions may require solidspacked in column reactors.

In some embodiments, the oxygenating agent used in the method of theinvention may be gaseous dioxygen. In some embodiments, the oxygenatingagent used in the method of the invention may be a solvent saturated indioxygen. In some embodiments, the oxygenating compound may be air. Insome embodiments, the oxygenating agent used in the method of theinvention may be a peroxide, such as hydrogen peroxide.

In some embodiments, a suitable first additive is a reductant such as aninorganic or an organic reductant. Suitable examples of organicreductants include, but are not restricted to, an aryl or alkylphosphine (such as triphenylphosphine or tris(2-carboxyethyl)phosphine),a phosphite (such as trimethylphosphite or triethylphosphite), or asulfide (such as glutathione, cysteine, methionine, dithiothritol or aderivative thereof). Suitable examples of an inorganic reductantinclude, but are not restricted to, a sulfite or metabisulfite derivedfrom an alkaline or alkaline earth metal. A typical example may includesodium or potassium sulfite.

In some embodiments, a second additive may be a base such as aninorganic or an organic base where step (a) is carried out under thermalconditions. Suitable examples of an organic base include, but are notrestricted to, an alkoxide (such as potassium tert butoxide or sodiumethoxide), trialkylamine (such as trimethylamine ordiisopropylethylamine), tetralkylammonium hydroxide (such as tetramethylammonium hydroxide or tetrabutyl ammonium hydroxide), guanidine (such astetramethylguanidine or Barton's base), 1,8-diazabicycloundec-7-ene(DBU) and/or a different nitrogenous heterocyclic base, or aphosphazene-type base. Suitable examples of an inorganic base include,but are not restricted to, carbonates or hydroxides derived fromalkaline or alkaline earth metals. A typical example may includepotassium or cesium hydroxides, or the corresponding carbonates. In someembodiments, the base optionally contains a co-reagent for enhancing theperformance of the reaction. In some embodiments, a suitable co-reagentis a metal cation ligand or scavenger. Suitable examples of metal cationligand or scavenger include but are not restricted to ethylene glycol,glycerol or derivatives, a glycol ether (such as ethylene glycolmonomethyl ether or dimethoxyethane), a cryptand (such as1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane), apolyethylenglycol (such as PEG-400) or a crown ether (such as1,4,7,10,13,16-hexaoxacyclooctadecane or1,4,7,10-tetraoxacyclododecane).

In some embodiments, a second additive may contain a base and a catalystwhere step (a) is carried out under photochemical conditions. Thecatalyst may be a photosensitizing molecule. A photosensitizingmolecule, also known as photosensitizer, is a molecule that produces achemical change in another molecule under light irradiation with aspecific wavelength. A catalyst is a component of chemical process thatis used in sub-stoichiometric amounts, such as 0.01 to 50 mol %, andpreferably between 0.1 and 5 mol %. Suitable photosensitizing moleculesinclude, but are not restricted to, Eosine Y, Methylene Blue, aporphyrin and a derivative thereof. In some embodiments, a suitablecatalyst is Rose Bengal or a derivative thereof. In some embodiments,the catalyst may be homogeneous or heterogeneous wherein a homogenouscatalyst is a catalyst that is completely soluble in the reactionmixture and a heterogeneous catalyst may be a homogenous catalystcovalently anchored on an insoluble substrate such as a nano- ormicrometric particle composed of silica, titania, or a polymericmaterial. In some embodiments, the catalyst may be anchored or coated onan internal wall of a micro- and/or meso-fluidic module. In someembodiments, the heterogeneous catalyst may be fed into a reactor withthe reaction mixture as a slurry or a stable colloidal solution.

In some embodiments, the method of the invention may use a protic polarsolvent such as a lower alkyl alcohol. In some embodiments, steps(a)-(c) may use the same solvent. In some embodiments, steps (a)-(c) maybe carried out in different solvents. In some embodiments, the solventremains unaltered in steps (a)-(c). In some embodiments, the method ofthe invention comprises performing steps (a) to (c) using the same flowof solvent which carries the various chemical intermediates through aflow reactor comprising micro- and/or meso-fluidic modules, where thesolvent has a high solubility of the chemicals in the flow. In someembodiments, the solvent provides a concentration of from 0.01 to 9mol/L, for example from 0.1 and 2 mol/L. In some embodiments, thesolvent may be ethanol. In some embodiments, a binary mixture of proticpolar and aprotic polar solvents can be used. Suitable aprotic polarsolvents include, but are not restricted to, propylene carbonate,dimethylformamide, and/or dimethylsulfoxide. Suitable binary solventmixtures have a composition volume ratio ranging from 1000:1 to 1:1protic/aprotic. In some embodiments, the aprotic polar solvent componentmay be a co-reactant. In some embodiments, the method of the inventionmay comprise a fifth additive which increases solubility of the secondadditive which is a base. In some embodiments, the fifth additive may bea phase transfer catalyst. Acceptable phase transfer catalysts include aquaternary ammonium salt, such as tetrabutylammonium chloride, ortrioctylmethylammonium chloride. In some embodiments, the phase transfercatalyst may be used in an amount from 0.01 mol % to 50 mol %, forexample from 1 mol % to 15 mol % with reference to a limiting reactant.It should be understood herein that the limiting reactant is thereference reagent (typically said in default (in mol), while the otherstoichiometric reagents are in excess). In some embodiments, thelimiting regent may be used in an amount of one molar equivalent; incomparison a reagent in excess is used in an amount of more than oneequivalent.

In some embodiments, steps (a), (b) and (c) of the method of theinvention may be telescoped by using a direct oxygenation of a compoundof formula (II) with mixing under thermal conditions with anitrogen-containing nucleophile. It has surprisingly been found thatsuch a method directly yields a compound of formula (I).

In some embodiments, steps (a), (b) and (c) of the method of theinvention may be telescoped by using photochemical oxygenation of acompound of formula (II) with mixing under thermal conditions with anitrogen-containing nucleophile. It has surprisingly been found thatsuch a method directly yields a compound of formula (I).

Herein “acyl” means a moiety of formula —C(O)—R⁵ where R⁵ represents ahydrogen atom or an alkyl, cycloalkyl or aryl group. “Amino” means amoiety of formula —NR⁶R⁷ where each of R⁶ and R⁷ independentlyrepresents a hydrogen atom or a lower alkyl group. “Alkoxy” means amoiety of formula —OR⁸ where R⁸ represents an alkyl group. In someembodiments, an alkoxy group may be a methoxy group (—OCH₃). “Alkyl”means a monovalent optionally substituted saturated straight- orbranched-chain hydrocarbon group containing from 1 to 8 carbon atoms. Insome embodiments, each alkyl group may, optionally, be substituted withone or more amino, hydroxyl or sulfhydryl groups. “Perfluoroalkyl” meansa monovalent optionally substituted saturated straight- orbranched-chain alkyl group containing from 1 to 8 carbon atoms in whichevery hydrogen has been replaced by a fluorine. “Aryl” means amonovalent optionally substituted mono-, bi- or tricyclic aromatichydrocarbon group having from 6 to 14 ring carbon atoms; for example aphenyl group. “Aryloxy” means a group of formula —OR⁹ wherein R⁹represents an aryl group. In some embodiments, an alkoxy group may bephenoxy. “Carboxyl” means a moiety of formula —C(O)OR¹⁰ wherein R¹⁰represents a hydrogen atom or an alkyl, cycloalkyl or aryl group.“Cycloalkyl” means a saturated optionally substituted monovalent mono-or bicyclic hydrocarbon moiety of from 3 to 10 ring carbon atoms. Insome embodiments, the cycloalkyl moiety contains from 4 to 8 ring carbonatoms, for example cycloalkyl may be cyclohexyl. “Halogen” means achlorine, fluorine, bromine or iodine atom. In some embodiments, halogenmay be a chlorine or bromine atom. “Heteroaryl” means a monovalentmonocyclic or bicyclic aromatic moiety of from 5 to 12 ring atomscontaining one, two, or three ring heteroatoms each of which isindependently selected from a nitrogen, oxygen, and/or sulfur atom,where the remaining ring atoms are each a carbon atom. “Hydroxyl” meansa —OH moiety. “Lower alkyl” means a saturated optionally substitutedstraight- or branched-chain hydrocarbon containing from 1 to 4 carbonatoms. In some embodiments, lower alkyl means a methyl moiety. “Nitro”means a —NO₂ group. “Cyano” means a —CN group. “Sulfhydryl” means a —SHgroup. “Sulfo” means a —SO₃H group. “Nitrogen-containing nucleophile”means any primary or secondary amine bearing alkyl, cycloalkyl or arylmoieties. “Prodrug” means any compound which releases a compound offormula (I) related to ketamine in vivo when such prodrug isadministered to a mammal. In some embodiments, a prodrug of a compoundof formula (I) may be prepared by modifying one or more functionalgroup(s) present in the compound of formula (I) such that the modifiedfunctional group(s) may be cleaved in vivo to release the correspondingcompound of formula (I). For example, a prodrug may include a compoundof formula (I) which has a hydroxy, amino, or sulfhydryl substituentwhich is bonded to a prodrug group such that the prodrug group may becleaved in vivo to generate a compound of formula (I) having a freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude an ester or carbamate of a hydroxy functional group in acompound of formula (I). “Organic base” means any nitrogenous organiccompound with basic properties such as, but not restricted to potassiumtert butoxide triethylamine, N,N-diisopropylethylamine,tetramethylguanidine, 1,8-diazabicycloundec-7-ene, tetramethylammoniumhydroxide,tetramethyl(tris(dimethylamino)phosphoranylidene)phosphorictriamid-Et-imin(phosphazene base P₂Et). “Inorganic base” means any inorganic saltderived from alkaline or alkaline earth metals with basic propertiessuch as, but not restricted to, NaOH, KOH, CsOH, Na₂CO₃, K₂CO₃ orCs₂CO₃, or a corresponding phosphates. “A reductant” means any inorganicor an organic molecules that could reduce oxygenated intermediates suchas peroxides or hydroperoxides, such as, but not restricted to,triphenylphosphine or tris(2-carboxyethyl)phosphine, ortrimethylphosphite, or glutathione, cysteine, methionine, dithiothreitolor derivatives thereof, sulfites or metabisulfites derived from alkalineor alkaline earth metals such as Na₂SO₃, K₂SO₃ or Na₂S₂O₅. “Metal cationligand or scavenger” means any organic ligand capable of stronglychelating a metal cation, such as, but not restricted to, ethyleneglycol, ethylene glycol monomethyl ether,1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane, PEG-400 or1,4,7,10,13,16-hexaoxacyclooctadecane. Photosensitizing moleculesinclude, but are not restricted to, Rose Bengal, Methylene Blue,porphyrin, and/or a derivative thereof. “Pharmaceutically acceptablesalt” means a conventional non-toxic salt, such as a salt derived froman inorganic acid (such as hydrochloric, hydrobromic, sulfuric,phosphoric, and/or nitric acid), an organic acid (such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,glutamic, aspartic, benzoic, salicylic, oxalic, and/or ascorbic acid). Apharmaceutically acceptable salt may be prepared in a conventionalmanner, e.g., by reacting a free base form of the compound of formula(I) with a suitable acid. “Precursor” means a compound of formula (II),a compound of formula (III), or a compound of formula (IV),

In some embodiments, the method of the invention uses a fluidic networkto generate intensified continuous-flow thermal conditions forsynthesizing a pharmaceutically active species (such as a compound offormula (I)), or a pharmaceutically active species precursor thereof(such as a compound of formula (III) or a compound of formula (IV))within a short reaction time such as a reaction time less than an hour,such as less than 30 minutes or less than 5 min by utilizing atemperature from room temperature to 300° C., for example from 30° C. to280° C. (or to 260° C. or to 220° C.), and a counter pressure rangingfrom 1 to 200 bar, for example from 10 to 100 bar (or to 70 bar).Herein, it should be understood that the counter-pressure is a pressurethat is set at a downstream part of the reactor by the operator (forexample, by using a pressure regulator). It sets the entire internalpressure of the reactor at the same value, and enables, for instance,use of a higher temperature than the boiling point of a solvent underatmospheric pressure (for example ethanol can be used as a liquid at200° C.).

In some embodiments, the present invention uses intensifiedcontinuous-flow photochemical conditions for synthesizing apharmaceutically active species precursor (such as a compound of formula(III)) using a short reaction time such as a reaction time less than 2hours, such as a reaction time less than 60 min by utilizing a lightsource emitting in the 250 to 850 nm wavelength range, for example from350 to 600 nm, and more specifically from 450 to 540 nm and atemperature from room temperature to 100° C., for example from 20° C. to45° C., and a counter pressure from 1 to 100 bar, for example from 2 to20 bar.

The present invention also discloses the integration or telescoping ofmultiple steps, including chemical and process steps for synthesizing apharmaceutically active species (such as a compound of formula (I)), orpharmaceutically active species precursor thereof (such as a compound offormula (III) or a compound of formula (IV)). In some embodiments, themethod of the invention uses a process parameter such as a flow ratewhich may be from 1 μL/min to 5000 mL/min, optionally from 100 μL/min to100 mL/min, and more specifically from 10 μL/min to 30 mL/min.

In some embodiments, the method of the invention uses a fluidic networkwhich comprises one or more fluidic modules, each associated with aspecific process step such as, but not restricted to, in-linepurification, in-line analysis and a chemical transformation. In someembodiments, a fluidic module may be constructed from a material with ahigh tolerance to a wide range of chemicals and a good tolerance to hightemperature and pressure, such as glass, specialty glass, quartz, fusedsilica, a perfluorinated polymer such as PFA, ETFE, PTFE, a ceramic suchas silicon carbide (SiC), and/or a metal such as copper, any grade ofstainless steel (SS), Hastelloy, nickel or and/or titanium. In someembodiments, the fluidic network may comprise a micro-fluidic moduleconstructed from a coil of a perfluorinated polymer with at least onedefined section and volume where the section is the internal diameter ofthe fluidic network and volume is the internal volume of at least a partof the fluidic network, optionally the volume of the entire fluidicnetwork. In some embodiments, a section of the reactor includes a SScolumn packed with a heterogeneous catalyst. In some embodiments, thefluidic network reactor comprises a meso-fluidic module constructed fromstainless steel (SS) with at least one defined section and volume. Insome embodiments, the fluidic network reactor comprises a meso-fluidicmodule constructed from SiC with at least one defined section andvolume. In some embodiments, a fluidic module may be constructed from atransparent material, such as glass, specialty glass such as Pyrexglass, quartz or fused silica, and/or a perfluorinated polymer such asPFA, ETFE or PTFE. In some embodiments, one or more fluidic module maybe constructed from a ceramic such as SiC or a metal such as SS. In someembodiments, one or more fluidic modules are constructed from aperfluorinated polymer such as PFA, ETFE or PTFE embedded in a metaltubular casing such as copper or SS tubing. In some embodiments, two ormore fluidic networks may be operated in series and/or in parallel; thetwo or more fluidic networks may be substantially identical.

The invention is illustrated with reference to the following Figures ofthe accompanying drawings which are not intended to limit the scope ofthe claimed invention:

FIG. 1 shows a schematic plan view of a first embodiment of a fluidicnetwork for use in the method of the invention;

FIG. 2 shows a schematic plan view of a second embodiment of a fluidicnetwork for use in the method of the invention; and

FIG. 3 shows a schematic plan view of a third embodiment of a fluidicnetwork for use in the method of the invention.

A first embodiment of a fluidic network for use in the method of theinvention is indicated generally at 10 on FIG. 1 . Fluidic network 10comprises 7 fluidic modules 102,103,105,108,109,110,112. Fluidic modules102,103,105,108,109,110,112 form three distinct fluidic assemblies I, IIand III. Fluidic assembly I comprises fluidic modules 102,103,105,fluidic assembly II comprises fluidic modules 108,109,110 and fluidicassembly III is composed of fluidic module 112. Fluidic modules102,103,105,108,109,110,112 may be connected in series, and fluidicassemblies I, II and III can be operated as a fully telescoped process.Alternatively, assemblies I, II and III can be disconnected and runindependently. The first fluidic module 102 of fluidic network 10 hastwo input connectors 100,101. The third fluidic module 105 of fluidicnetwork 10 has one input connector 104 and one output connector 106. Thefourth fluidic module 108 of fluidic network 10 has one input connector107. The sixth fluidic module 110 of fluidic network 10 has one outputconnector 111. The last module 112 of fluidic network 10 has one outputconnectors 113.

The fluidic reactor network 10 comprises a first module 102 and a secondmodule 103 fluidically connected to the first module 102, and a thirdmodule 105 fluidically connected to the second module 103 in series, anda fourth module 108 fluidically connected to the third module 105 inseries, and a fifth module 109 fluidically connected to the fourthmodule 108 in series, and a sixth module 110 fluidically connected tothe fifth module 109 in series, and a seventh module 112 fluidicallyconnected to the sixth module 110 in series. Additional fluidic modulesmay be connected in series to include additional unit operations such asin-line purification, in-line analysis or chemical transformation. Insome embodiments, in-line analysis includes in-line spectroscopicmethods, for example in-line IR. In some embodiments, the fluidicreactor network may be duplicated and run in parallel to increaseproductivity. In some embodiments, the internal diameter of the fluidicreactor network can be significantly increased for increasing theproductivity.

The first fluidic module 102 is dedicated to mixing two fluids which areinput into module 102 by input connectors 100,101 where the two fluidscontain at least a compound of formula (II) and an oxygenating agent. Inan alternative embodiment, fluidic module 102 may be composed of one ormore embedded mixers or one or more independent mixing elements, such asan arrow-head mixer, a T-mixer, Y-mixer, cross-junction and/or staticmicromixer, made either of glass, stainless steel, polymeric materialand/or a ceramic material, or a membrane or a porous material, or acombination of two or more of the aforementioned materials.

The second fluidic module 103 has an integrated heat exchanger which maybe operated at a temperature ranging from −10° C. to 200° C. In analternative embodiment, a thermostat or a cryostat or anythermoregulatory device may be utilized to control the temperature offluidic module 103. In an alternative embodiment, fluidic module 103 mayhave more than one section such that some sections of fluidic module 103may be operated at different temperatures at the same time, for exampleat temperature above 100° C. for a first section of fluidic module 103,and below 50° C. in a last section of fluidic module 103. In analternative embodiment, fluidic module 103 may be operated at a pressureranging from 1 to 30 bar. In an alternative embodiment, fluidic module103 has an integrated static mixer. In an alternative embodiment, theinternal volume of fluidic module 103 may be increased by inserting anadditional fluidic element. In an alternative embodiment, fluidic module103 is constructed from a transparent material enabling the irradiationof the internal volume of fluidic module 103. In an alternativeembodiment, fluidic module 103 has an integrated light source such as afluorescent light source, low/medium/high pressure mercury vapor light,a halogen light or LEDs with appropriate wavelengths ranging from 250 to850 nm wavelength range, for example from 350 to 600 nm, and morespecifically from 450 to 540 nm.

The third fluidic module 105 is composed of an inlet for an additivefluid 104, a mixing area, a separation device, an outlet 106 for a wastestream and a back-pressure regulator on each outlet set wherein theback-pressure regulators have a cracking pressure ranging from 1 to 30bar, for example from 5 to 15 bar. In an alternative embodiment, theadditive fluid 104 contains a reductant in an appropriate solvent. Themixing area may be composed of one or more mixing elements such as anarrow-head mixer, T-mixer, Y-mixer, cross-junction or static micromixer,made either of glass, stainless steel, a polymeric material and/or aceramic material, or a combination of two or more of the aforementionedmaterials. The mixing area may also be composed of a packed-bed reactorpacked with beads made of an inert material such as glass, stainlesssteel or ceramic with a diameter ranging from 0.05 to 1 mm, for examplefrom 0.1 to 0.2 mm. In an alternative embodiment, fluidic module 105 iscomposed of one or more elements for performing quench, liquid-liquidextraction, liquid-liquid separation, gas-liquid separation involving amembrane or a settling tank. In an alternative embodiment, the outlet106 is redirected to a waste tank which contains a gas. In analternative embodiment, in-line analysis including, but not restrictedto, in-line IR monitoring or other spectroscopic methods, may beintegrated in fluidic module 105. In an alternative embodiment, fluidicmodule 105 only regulates the upstream pressure, ranging from 1 to 30bar, for example from 5 to 15 bar.

The fourth fluidic module 108 is dedicated to adding fluids via inlet107 to the main organic effluent from upstream fluidic module 105, andto mixing these two fluids that contain at least a pharmaceuticallyactive species precursor such as a hydroxylated compound of formula(III). Fluid 107 may comprise at least a nitrogen-containingnucleophile. In an alternative embodiment, fluidic module 108 maycomprise an embedded mixer or an inserted independent fluidic element,such as an arrow-head mixer, T-mixer, Y-mixer, cross-junction or staticmicromixer, made of glass, stainless steel, polymeric material and/orceramic.

The fifth fluidic module 109 is integrated with a heat exchanger, andmay be operated at a temperature ranging from 20 to 250° C., for examplefrom 80 to 160° C. In an alternative embodiment, a thermostat or acryostat or other thermoregulatory device may be utilized to control thetemperature of fluidic module 109. In an alternative embodiment, fluidicmodule 108 may comprise two or more sections such that one or moresections of fluidic module 108 may each be operated at differenttemperatures at the same time, for example at a temperature above 50° C.for the first section of fluidic module 109, and at a temperature below200° C. in the last section of fluidic element 109. In an alternativeembodiment, fluidic module 109 has integrated static mixers. In analternative embodiment, the internal volume of fluidic module 109 may beincreased by inserting one or more additional fluidic elements. In analternative embodiment, fluidic module 109 may comprises an integratedback-pressure regulator having a cracking pressure setting ranging from1 to 30 bar, for example from 4 and 15 bar. In an alternativeembodiment, fluidic modules 108,109 can be disconnected from fluidicmodule 105, and the corresponding processes may be run independently.

The sixth fluidic module 110 integrates additional downstream operationsis composed of an outlet 111 for a waste stream and a back-pressureregulator on each outlet set wherein the back-pressure regulators have acracking pressure ranging from 1 to 30 bar, for example from 5 to 15bar. In an alternative embodiment, fluidic module 110 is composed of oneor more elements for performing quench, liquid-liquid extraction,liquid-liquid separation, gas-liquid separation involving a membrane ora settling tank. In an alternative embodiment, the outlet 111 isredirected to a waste tank which contains a gas and/or a liquid. In analternative embodiment, in-line analysis including, but not restrictedto, in-line IR monitoring or other spectroscopic methods, may beintegrated in fluidic module 110. In an alternative embodiment, fluidicmodule 110 only regulates the upstream pressure, ranging from 1 to 30bar, for example from 5 to 15 bar.

The seventh fluidic module 112 is integrated with a heat exchanger and ahigh pressure pumping system, and may be operated at a temperatureranging from 20 to 300° C., for example from 120 to 280° C. In analternative embodiment, a thermostat or a cryostat or otherthermoregulatory device may be utilized to control the temperature offluidic module 112. In an alternative embodiment, fluidic module 112 maycomprise two or more sections such that one or more sections of fluidicmodule 112 may each be operated at different temperatures at the sametime, for example at a temperature above 100° C. for the first sectionof fluidic module 112, and at a temperature below 200° C. in the lastsection of fluidic element 112. In an alternative embodiment, theinternal volume of fluidic module 112 may be increased by inserting oneor more additional fluidic elements. In an alternative embodiment,fluidic module 112 may comprise an integrated back-pressure regulatorhaving a cracking pressure setting ranging from 1 to 200 bar, forexample from 20 to 100 bar. In an alternative embodiment, fluidic module112 can be disconnected from fluidic module 110, and the correspondingprocesses may be run independently. In an alternative embodiment,fluidic module 112 integrates one or more additional downstreamoperations such as liquid-liquid extraction, liquid-liquid separation,liquid-solid separation, crystallization, mixing with another fluidcontaining at least one solvent, formulation, temperature control suchas but not restricted to cooling, crystallization, automated collectionand/or in-line analysis. Fluid 113 comprises an organic solvent, and/ora pharmaceutically active species precursor in solution and/or apharmaceutically active species in solution and/or a formulation ofpharmaceutically active species in solution. In an alternativeembodiment, fluid 113 comprises a carrier fluid comprising an organicsolvent, and/or organic impurities in solution, and/or apharmaceutically active species precursor in suspension and/or apharmaceutically active species in suspension and/or a formulation ofpharmaceutically active species in suspension.

A fluidic network according to a second embodiment of the invention foruse in the method of the invention is indicated generally at 20 on FIG.2 of the accompanying drawings. Fluidic network 20 comprises a firstmodule 202 and a second module 203 fluidically connected to the firstmodule 202, and a third module 205 fluidically connected to the secondmodule 203 in series. One or more additional fluidic modules may beconnected in series to include one or more additional unit operationssuch as in-line purification, in-line analysis or chemicaltransformation. In some embodiments, in-line analysis includes in-linespectroscopic methods, for example in-line IR. In some embodiments, thefluidic reactor network may be duplicated and run in parallel toincrease productivity. In some embodiments, the internal diameter of thefluidic reactor network can be significantly increased for increasingthe productivity.

The first fluidic module 202 is dedicated to mixing two fluids which areinput into module 202 by input connectors 200,201 where the two fluidscontain at least a compound of formula (IV) which is a hydroxylatedimino-arylcycloalkylamine precursor and an acid in a solvent. In analternative embodiment, fluidic module 202 may be composed of one ormore embedded mixers or independent mixing elements, such as anarrow-head mixer, T-mixer, Y-mixer, cross-junction and/or staticmicromixer, made of glass, stainless steel, polymeric material and/or aceramic material, or a combination of two or more of the aforementionedmaterials.

The second fluidic module 203 has an integrated heat exchanger which maybe operated at a temperature ranging from 20 to 250° C., for examplefrom 120 to 220° C. In an alternative embodiment, a thermostat or acryostat or any thermoregulatory device may be utilized to control thetemperature of fluidic module 203. In an alternative embodiment, fluidicmodule 203 may have more than one section such that some sections offluidic module 203 may be operated at different temperatures at the sametime, for example at a temperature above 100° C. for a first section offluidic module 203, and below 250° C. in a last section of fluidicmodule 203. In an alternative embodiment, fluidic module 203 may beoperated at a pressure ranging from 1 to 100 bar, for example from 20 to70 bar. In an alternative embodiment, fluidic module 203 has anintegrated static mixer. In an alternative embodiment, the internalvolume of fluidic module 203 may be increased by inserting an additionalfluidic element.

The third fluidic module 205 is composed of an inlet for an additivefluid 204, a mixing area, and a back-pressure regulator with a crackingpressure ranging from 1 to 100 bar, for example from 20 to 70 bar. In analternative embodiment, the additive fluid 204 contains an antisolvent.The mixing area may be composed of one or more mixing elements such asan arrow-head mixer, T-mixer, Y-mixer, cross-junction and/or staticmicromixer, made either of glass, stainless steel, a polymeric materialand/or a ceramic material, or a combination of two or more of theaforementioned materials. In an alternative embodiment, fluidic module205 integrates one or more additional downstream operations such asliquid-liquid extraction, liquid-liquid separation, liquid-solidseparation, crystallization, mixing with another fluid containing atleast one solvent, formulation, temperature control such as but notrestricted to cooling, crystallization, automated collection and/orin-line analysis. Fluid 206 comprises an organic solvent, and/or apharmaceutically active species precursor in solution and/or apharmaceutically active species in solution and/or a formulation ofpharmaceutically active species in solution. In an alternativeembodiment, fluid 206 comprises a carrier fluid comprising an organicsolvent, and/or organic impurities in solution, and/or apharmaceutically active species precursor in suspension and/or apharmaceutically active species in suspension and/or a formulation ofpharmaceutically active species in suspension.

A fluidic network according to a third embodiment of the invention foruse in the method of the invention is indicated generally at 30 on FIG.3 of the accompanying drawings. Fluidic network 30 comprises a firstmodule 302 and a second module 303 fluidically connected to the firstmodule 302, and a third module 304 fluidically connected to the secondmodule 303 in series. Additional fluidic modules may be connected inseries to include one or more additional unit operations such as in-linepurification, in-line analysis or chemical transformation. In someembodiments, in-line analysis includes an in-line spectroscopic method,for example in-line IR. In some embodiments, the fluidic reactor networkmay be duplicated and run in parallel to increase productivity.

The first fluidic module 302 is dedicated to mixing two fluids which areinput into module 302 by input connectors 300,301 where the two fluidscontain at least a compound of formula (III) which is a hydroxylatedarylcycloalkylamine precursor and a nitrogen-containing nucleophile in asolvent or a mixture of solvents. In an alternative embodiment, fluidicmodule 302 may be composed of one or more embedded mixers or independentmixing elements, such as an arrow-head mixer, T-mixer, Y-mixer,cross-junction and/or static micromixer, made of glass, stainless steel,a polymeric material and/or a ceramic material, or a combination of twoor more of the aforementioned materials.

The second fluidic module 303 has an integrated heat exchanger which maybe operated at a temperature ranging from 20 to 250° C., for examplefrom 80 to 160° C. In an alternative embodiment, a thermostat or acryostat or any thermoregulatory device may be utilized to control thetemperature of fluidic module 303. In an alternative embodiment, fluidicmodule 303 may be operated at a pressure ranging from 1 to 200 bar, forexample from 20 to 100 bar. In an alternative embodiment, fluidic module303 has an integrated static mixer. In an alternative embodiment, theinternal volume of fluidic module 303 may be increased by inserting anadditional fluidic element.

The third fluidic module 304 has an integrated heat exchanger which maybe operated at a temperature ranging from 20 to 300° C., for examplefrom 160 to 280° C. In an alternative embodiment, a thermostat or acryostat or any thermoregulatory device may be utilized to control thetemperature of fluidic module 304. In an alternative embodiment, fluidicmodule 304 may be operated at a pressure ranging from 1 to 200 bar, forexample from 20 to 100 bar. In an alternative embodiment, fluidic module304 has an integrated static mixer. In an alternative embodiment, theinternal volume of fluidic module 304 may be increased by inserting anadditional fluidic element. In an alternative embodiment, fluidic module304 integrates one or more additional downstream operations such asliquid-liquid extraction, liquid-liquid separation, liquid-solidseparation, crystallization, mixing with another fluid containing atleast one solvent, formulation, temperature control such as but notrestricted to cooling, crystallization, automated collection and/orin-line analysis. Fluid 305 comprises an organic solvent, and/or apharmaceutically active species precursor in solution and/or apharmaceutically active species in solution and/or a formulation ofpharmaceutically active species in solution. In an alternativeembodiment, fluid 305 comprises a carrier fluid comprising an organicsolvent, and/or organic impurities in solution, and/or apharmaceutically active species precursor in suspension and/or apharmaceutically active species in suspension and/or a formulation ofpharmaceutically active species in suspension.

The invention will now be illustrated by reference to the followingExamples which are not intended to limit the scope of the inventionclaimed.

EXAMPLES

Preparative Example 1: Preparation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) in Batch

3.04 g (125 mmol, 1 eq.) of magnesium powder were charged in aflame-dried 500 mL round-bottom two-neck flask equipped with acondenser, and covered with 100 mL of freshly distilled diethyl ether.To the suspension were added dropwise 20.5 g (0.138 mol, 1.1 eq.) ofbromocyclopentane over 1 h, and the solution was maintained at a gentlereflux upon disappearance of the magnesium. Then, a solution of 0.179 g(1.25 mmol, 0.01 eq.) of copper (I) bromide (CuBr) and 0.280 g of(1,4-diazabicyclo[2.2.2]octane) DABCO (2.5 mmol, 0.02 eq.) in 10 mL ofdry diethyl ether was added in one portion to the Grignard reagent. Inanother flame-dried Schlenk tube, a solution of 17.2 g of2-chlorobenzonitrile (125 mmol, 1 eq.) in 100 mL of dry diethyl etherwas prepared, and next cannulated to the Grignard reagent. The resultingmixture was stirred overnight. Afterwards, the reaction mixture wascooled in an ice-bath, and 100 mL of aqueous HCl (1.2 M) were added. Thesolution was stirred for 6 h, and then extracted with 5×40 mL of diethylether. The organic extracts were washed with 50 mL of brine, dried overanhydrous magnesium sulfate, filtrated and concentrated under reducedpressure. 13.04 g of 2-chlorophenyl)(cyclopentyl)methanone (IIa) wereobtained after bulb-to-bulb distillation (50% overall yield).Characterization ¹H NMR (250 MHz, CDCl₃) 7.51-7.14 (m, 1H), 3.52 (p,J=7.8 Hz, 0H), 1.99-1.74 (m, 1H), 1.73-1.44 (m, 1H). ¹³C NMR (100.6 MHz,CDCl₃) 206.8, 140.3, 130.6, 29.4, 26.0.

Example 2: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in batch

A flame-dried 500 mL round-bottom flask was charged with a secondadditive in the form of a base which is cesium carbonate (Cs₂CO₃) (3.16g, 9.71 mmol, 0.2 eq.) and a first additive in the form of a reductantwhich is triethyl phosphite (P(OEt)₃) (16.5 mL, 96.22 mmol, 2 eq.),(2-chlorophenyl)(cyclopentyl)methanone (IIa) (10.05 g, 48.16 mmol, 1eq.) and dimethyl sulfoxide (DMSO) (100 mL). The resulting suspensionwas stirred under an oxygen (O₂) atmosphere for 24 h at roomtemperature. The solution was next diluted with ethyl acetate (250 mL),washed with 200 mL of brine, extracted with ethyl acetate (3×100 mL).The resulting solution in ethyl acetate was dried over magnesium sulfate(MgSO₄), filtrated and concentrate under reduced pressure. The productwas purified on silica gel by chromatography, and compound(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) was obtained as apale-yellow oil (10.43 g, 96% yield, 99% conversion). Characterization¹H NMR (400 MHz, CDCl₃) 7.42 (dd, J=8.0, 1.4 Hz, 1H), 7.37 (td, J=8.0,7.6, 1.8 Hz, 1H), 7.31 (td, J=7.4, 1.4 Hz, 1H), 7.26 (dd, J=7.5, 1.8 Hz,1H), 3.24 (s, 1H), 2.22-2.07 (m, 2H), 2.00-1.84 (m, 4H), 1.76 (m, 2H).¹³C NMR (100.6 MHz, CDCl₃) 209.4, 138.3, 130.7, 130.3, 129.9, 127.2,126.4, 88.5, 39.3, 24.3. ESI: [M+Na]⁺ calcd: 247.04963, found:247.04961.

Example 3: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Batch withPhoto-Irradiation

A flame-dried 500 mL round-bottom flask was charged with(2-chlorophenyl)(cyclopentyl)methanone (IIa) (10.05 g, 48.16 mmol, 1eq.) and a second additive containing a base which is cesium carbonate(Cs₂CO₃) (3.16 g, 9.71 mmol, 0.2 eq.) and a photosensitizer which isRose Bengal (5 mol %) and ethanol (100 mL). The resulting suspension wasstirred under an oxygen (O₂) atmosphere for 10 h at room temperatureupon irradiation at 540 nm (12 LEDs). A solution of a first additivewhich is a reductant in the form of triethyl phosphite (P(OEt)₃) (16.5mL, 96.22 mmol, 2 eq.) in ethanol was added, and the solution wasstirred for 1 h at room temperature. The solvent was removed underreduced pressure, and compound(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) was obtained in30% conversion.

Example 4: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Batch withPotassium Tert Butoxide as Second Additive

A flame-dried 500 mL round-bottom flask was charged with a secondadditive in the form of a base which is potassium ter butoxide (KOtBu)(1.09 g, 9.71 mmol, 0.2 eq.) and a first additive in the form of areductant which is triethyl phosphite (P(OEt)3) (16.5 mL, 96.22 mmol, 2eq.), (2-chlorophenyl)(cyclopentyl)methanone (IIa) (10.05 g, 48.16 mmol,1 eq.) and ethanol (100 mL). The resulting suspension was stirred underan oxygen (O₂) atmosphere for 24 h at room temperature. The solvent wasevaporated, and the residue was diluted with ethyl acetate (250 mL), andwashed with 200 mL of brine. The resulting solution in ethyl acetate wasdried over magnesium sulfate (MgSO₄), filtrated and concentrate underreduced pressure. Compound(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) was obtained as apale-yellow oil with 99% conversion and 27% selectivity.

Example 5: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withCesium Carbonate as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(0.1 M) and a second additive in the form of a base which is cesiumcarbonate (Cs₂CO₃) (20 mol %) and in ethanol containing dimethylsulfoxide (DMSO) (5% volume) was pumped at a flow rate of 0.1 mL min⁻¹and mixed with a stream of oxygen gas (10 mL·min⁻¹). Oxygen (AirLiquide,Alphagaz 1) and the liquid feed solution were mixed through a staticmixer (T-Mixer, IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″ o.d.tubing, 0.02″ through hole) placed upstream the reaction coil. Theresulting reaction mixture was reacted for 15 min in the reaction coilunder thermal conditions at 25° C. (room temperature). Thecontinuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils arounda thermoregulated aluminum cylinder. A back-pressure regulator set at250 psi was inserted downstream. The reactor effluent was collected,quenched with a first additive which is a reductant in the form ofsodium metabisulfite (Na₂S₂O₅) and processed, affording compound(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) was obtained in40% conversion.

Example 6: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPhosphazene Base P2-Et as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(1 M) a first additive in the form of a reductant which is triethylphosphite ((P(OEt)₃), 110 mol %) and a second additive in the form of abase which is phosphazene base P₂-Et (P₂-Et) (50 mol %) in ethanol waspumped at a flow rate of 0.2 mL min⁻¹ and mixed with a stream of oxygengas (10 mL·min⁻¹). Oxygen (AirLiquide, Alphagaz 1) and the liquid feedsolution were mixed through a static mixer (T-Mixer, IDEX-Upchurch,natural PEEK ¼-28 thread for 1/16″ o.d. tubing, 0.02″ through hole)placed upstream the reaction coil. The resulting reaction mixture wasreacted for 5 min in the reaction coil under thermal conditions at 25°C. The continuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 160 psi wasinserted downstream. The reactor effluent was collected and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in 95% conversion (98% selectivity).

Example 7: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPotassium Tert Butoxide as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(1 M), a first additive in the form of a reductant which is triethylphosphite ((P(OEt)₃), 110 mol %) and a second additive in the form of abase which is potassium tert butoxide (50 mol %) in ethanol was pumpedat a flow rate of 0.2 mL min⁻¹ and mixed with a stream of oxygen gas (10mL·min⁻¹). Oxygen (AirLiquide, Alphagaz 1) and the liquid feed solutionwere mixed through a static mixer (T-Mixer, IDEX-Upchurch, natural PEEK¼-28 thread for 1/16″ o.d. tubing, 0.02″ through hole) placed upstreamthe reaction coil. The resulting reaction mixture was reacted for 5 minin the reaction coil under thermal conditions at 35° C. Thecontinuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 160 psi wasinserted downstream. The reactor effluent was collected and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in >95% conversion (50% selectivity).

Example 8: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPotassium Tert Butoxide and 18-C-6 as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(1 M), a first additive in the form of a reductant which is triethylphosphite ((P(OEt)₃), 110 mol %) and a second additive containing a basewhich is potassium tert butoxide (50 mol %) and a metal cation scavengerwhich is 1,4,7,10,13,16-hexaoxacyclooctadecane (18-C-6, 50 mol %) inethanol was pumped at a flow rate of 0.2 mL min⁻¹ and mixed with astream of oxygen gas (10 mL·min⁻¹). Oxygen (AirLiquide, Alphagaz 1) andthe liquid feed solution were mixed through a static mixer (T-Mixer,IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″ o.d. tubing, 0.02″through hole) placed upstream the reaction coil. The resulting reactionmixture was reacted for 5 min in the reaction coil under thermalconditions at 30° C. The continuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 160 psi wasinserted downstream. The reactor effluent was collected and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in >99% conversion (96% selectivity).

Example 9: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPotassium Hydroxide as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(1 M), a first additive in the form of a reductant which is triethylphosphite ((P(OEt)₃), 110 mol %) and a second additive in the form of abase which is potassium hydroxide (50 mol %) in ethanol was pumped at aflow rate of 0.2 mL min⁻¹ and mixed with a stream of oxygen gas (10mL·min⁻¹). Oxygen (AirLiquide, Alphagaz 1) and the liquid feed solutionwere mixed through a static mixer (T-Mixer, IDEX-Upchurch, natural PEEK¼-28 thread for 1/16″ o.d. tubing, 0.02″ through hole) placed upstreamthe reaction coil. The resulting reaction mixture was reacted for 5 minin the reaction coil under thermal conditions at 30° C. Thecontinuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 160 psi wasinserted downstream. The reactor effluent was collected and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in >88% conversion (64% selectivity).

Example 10: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPotassium Hydroxide and with 18-C-6 as Second Additive

The reaction was carried out as in Example 9 except that a metal cationscavenger which is 1,4,7,10,13,16-hexaoxacyclooctadecane (18-C-6, 50 mol%) in ethanol was added at a flow rate of 0.2 mL min⁻¹ and mixed with astream of oxygen gas (10 mL·min⁻¹), affording compound(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in >97%conversion (96% selectivity).

Example 11: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withTetramethylammonium Hydroxide as Second Additive

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(1 M), a first additive in the form of a reductant which is triethylphosphite ((P(OEt)₃), 110 mol %) and a second additive in the form of abase which is tetramethylammonium hydroxide (50 mol %) in ethanol waspumped at a flow rate of 0.2 mL min⁻¹ and mixed with a stream of oxygengas (10 mL·min⁻¹). Oxygen (AirLiquide, Alphagaz 1) and the liquid feedsolution were mixed through a static mixer (T-Mixer, IDEX-Upchurch,natural PEEK ¼-28 thread for 1/16″ o.d. tubing, 0.02″ through hole)placed upstream the reaction coil. The resulting reaction mixture wasreacted for 5 min in the reaction coil under thermal conditions at 30°C. The continuous-flow setup for the oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 160 psi wasinserted downstream. The reactor effluent was collected and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in >99% conversion (91% selectivity).

Examples 6 to 11 show a superior effect of this reaction step in flowversus this reaction step in batch (cfr examples 2 and 4): the reactiontime is drastically reduced to 5 minutes while excellent yield andselectivity are obtained.

Example 12: Preparation of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) in Flow withPhoto-Irradiation

A feed solution containing (2-chlorophenyl)(cyclopentyl)methanone (IIa)(0.1 M) in ethanol and a second additive containing a base which iscesium carbonate (Cs₂CO₃) (20 mol %) and a photosensitizer which is RoseBengal (5 mol %) was pumped at a flow rate of 0.1 mL min⁻¹ and mixedwith a stream of oxygen gas (10 mL·min⁻¹). Oxygen (AirLiquide,Alphagaz 1) and the liquid feed solution were mixed through a staticmixer (T-Mixer, IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″ o.d.tubing, 0.02″ through hole) placed upstream the irradiation coil. Theresulting reaction mixture was reacted for 15 min in the irradiationcoil. The continuous-flow setup for the photocatalytic oxygenation of(2-chlorophenyl)(cyclopentyl)methanone (IIa) was constructed from a highpurity PFA capillary (800 μm internal diameter) wrapped in coils arounda reflective, thermoregulated aluminum cylinder. The PFA coils weresurrounded by 4 adjustable heat-sink integrated pillars each supporting3 high power LEDs (540 nm, LZ1-00G102, Led Engin). The LEDs were mountedto face towards the PFA coil wrapped around the central cylinder. Aback-pressure regulator set at 250 psi was inserted downstream. Thereactor effluent was collected, quenched with a first additive which isa reductant in the form of sodium metabisulfite (Na₂S₂O₅) and processed,affording compound (2-chlorophenyl)(1-hydroxycyclopentyl)methanone(IIIa) in 40% conversion.

Compared to example 3 in batch, an increase in conversion was observedfor this example in flow with photo-irradiation, together with a drasticreduction of reaction time (15 min versus 10 hours).

Example 13: Preparation of1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in Batch

A 250 mL round-bottom flask was charged with 20 g (90 mmol, 1 eq.) of(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) and 60 mL (90mmol, 5 eq.) of a 33 wt.-% solution of a nitrogen-containing nucleophilein the form of methylamine (MeNH₂) in absolute ethanol, and hermeticallysealed. The resulting mixture was stirred at room temperature for 6days. The solvent was then removed under reduced pressure, and1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) was obtainedas a pale-yellow solid was obtained (97% yield). Characterization ¹H NMR(400 MHz, CDCl₃) 7.50-7.45 (m, 1H), 7.40-7.31 (m, 2H), 7.11-7.06 (m,1H), 5.84-5.02 (m, 1H), 3.03 (s, 3H), 2.02-1.86 (m, 4H), 1.85-1.75 (m,1H), 1.74-1.49 (m, 3H). ¹³C NMR (100.6 MHz, CDCl₃) 173.0, 134.0, 129.9,129.8, 128.9, 126.6, 84.3, 39.4, 38.3, 37.9, 23.6, 23.4. ESI-HRMS:[M+H]⁺ calcd: 238.09932, found: 238.09920.

Example 14: Preparation of1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in Flow

A feed solution containing(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) (0.36 M) inethanol was pumped at a flow rate of 0.1 mL min⁻¹ and mixed through astatic mixer (T-Mixer, IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″o.d. tubing, 0.02″ through hole) with a stream containing anitrogen-containing nucleophile in the form of methylamine (MeNH₂) inethanol. The static mixer was placed upstream the reaction coil. Theresulting reaction mixture was reacted for 4-15 min in the reaction coil(Table 1). The continuous-flow setup was constructed from a high purityPFA capillary (800 μm internal diameter) wrapped in coils in athermoregulated device. A back-pressure regulator set at 250 psi wasinserted downstream. The reactor effluent was collected and concentratedto afford 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in11-85% conversion.

TABLE 1 MeNH₂ Residence time Temperature Conversion Entry (equiv.) (min)(° C.) (%) 1 10 4 80 11 2 10 4 100 15 3 10 4 120 29 4 5 6 120 33 5 5 11120 55 6 5 15 130 85

Example 15: Preparation of1[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in Flow withTriisopropyl Borate as Third Additive

A feed solution containing(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) (4.48 M) and athird additive in the form of triisopropyl borate (200 mol %) in ethanolwas pumped at a flow rate of 0.7 mL min⁻¹ and mixed through a staticmixer (T-Mixer, IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″ o.d.tubing, 0.02″ through hole) with a stream containing anitrogen-containing nucleophile in the form of methylamine (MeNH₂) inethanol (33%) injected at a flow rate of 0.8 mL min⁻¹. The static mixerwas placed upstream the reaction coil. The resulting reaction mixturewas reacted for 1 min in the reaction coil at 60° C. The continuous-flowsetup was constructed from a high purity PFA capillary (800 μm internaldiameter) wrapped in coils in a thermoregulated device. A back-pressureregulator set at 75 psi was inserted downstream. The reactor effluentwas collected and concentrated to afford1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in 99%conversion.

Examples 14 and 15 show a superior effect of this reaction step in flowversus this reaction step in batch (cfr example 13): the reaction timeis drastically reduced while maintaining an excellent yield.

Example 16: Preparation of(R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, (R,S)-ketamineFree Base (Rac-1) Under Microwave Irradiation as a Mimic of ContinuousFlow Conditions

5 mL of a solution of1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) in absoluteethanol (0.42 M) was heated at temperatures ranging from 140 to 180° C.under microwave irradiation in a 20 mL batch vial for reaction timesranging from 2.5 to 30 min under 20 bar of pressure (Table 2) in thepresence of a fourth additive in the form of a heterogeneous acidcatalyst (Montmorillonite K10). The reaction mixture was filtered andthe solvent was evaporated, affording (R,S)-ketamine rac-1 free base in23-81% conversion (99% selectivity). Characterization ¹H NMR (400 MHz,CDCl₃) 7.55 (dd, J=7.8, 1.7 Hz, 1H), 7.38 (dd, J=7.8, 1.5 Hz, 1H), 7.32(td, J=7.6, 1.5 Hz, 1H), 7.28-7.21 (m, 1H), 2.87-2.70 (m, 1H), 2.59-2.41(m, 2H), 2.11 (s, 3H), 2.00 (ddt, J=12.1, 6.9, 4.8 Hz, 1H), 1.94-1.81(m, 1H), 1.81-1.68 (m, 3H). ¹³C NMR (100.6 MHz, CDCl₃) 209.2, 137.9,133.8, 131.2, 129.4, 128.7, 126.6, 70.2, 39.6, 38.7, 29.1, 28.1, 21.9.ESI-HRMS: [M+H]⁺ calcd: 238.09932, found: 238.09936.

TABLE 2 Catalyst Residence (loading in time Temperature ConversionSelectivity Entry mol %) (min) (° C.) (%) (%) 1 K10 (100) 15 140 23 99 2K10 (100) 15 160 56 99 3 K10 (100) 15 180 81 99 4 K10 (100) 30 180 80 995 / 15 180 43 99

Example 17: Preparation of(R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, (R,S)-ketamineFree Base (rac-1) in Flow

A solution of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa)in absolute ethanol (0.36 M) was injected at a flow rate of 0.1 mL min⁻¹with a HPLC pump toward a stainless steel microfluidic reactor loop (2.5mL internal volume, corresponding to a residence time of 25 min). Thereactor was operated under thermal conditions at 180° C. under 250 psiof counter-pressure. The reactor effluent was collected and processed,affording (R,S)-ketamine rac-1 free base in 30% yield.

Example 18: Preparation of(R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, (R,S)-ketamineFree Base (rac-1) in Flow, with Toluene as an Alternative Solvent

A solution of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa)in toluene (0.36 M) was injected at a flow rate of 0.1 mL min⁻¹ with aHPLC pump toward a stainless steel microfluidic reactor loop (2.5 mLinternal volume, corresponding to a residence time of 25 min). Thereactor was operated at various temperatures under 1000 psi ofcounter-pressure (Table 3). The reactor effluent was collected andprocessed, affording (R,S)-ketamine rac-1 free base in 12-70% yield.

TABLE 3 Residence time Temperature Yield Entry (min) (° C.) (%) 1 25 18012 2 25 200 30 3 25 220 70 4 25 240 decomposition 5 25 260 decomposition6  5 260 decomposition

Example 19: Preparation of(R,S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone, (R,S)-ketamineFree Base (Rac-1) in Flow, with Montmorillonite K10 as Fourth Additive

1 L of 1[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa) inethanol (0.42 M) was pumped at a flow rate of 0.8 mL min⁻¹ was reactedat 180° C. for a residence time of 15 min in a stainless steel columnpacked with 3.7 of Montmorillonite K10 as a heterogeneous catalyst. Thereactor was operated at various temperatures under 500 psi ofcounter-pressure (Table 2). The reactor effluent was collected andprocessed, affording (R,S)-ketamine rac-1 free base in 75% conversionand >99% selectivity. Compared to example 16 under microwaveirradiation, the flow conditions enable treatment of a much highervolume of sample (up to 1 L and even up to 10 L without restrictions).

Example 20: Preparation of(R,S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone, (R,S)-ketamineFree Base (rac-1) in Flow, Telescoping Two Steps

A feed solution containing(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa) (0.36 M) inethanol was pumped at a flow rate of 0.1 mL min⁻¹ and mixed through astatic mixer (T-Mixer, IDEX-Upchurch, natural PEEK ¼-28 thread for 1/16″o.d. tubing, 0.02″ through hole) with a stream containing anitrogen-containing nucleophile in the form of methylamine (MeNH₂) inethanol. The static mixer was placed upstream the reaction coil. Theresulting reaction mixture was reacted for 15 min in the reaction coiloperated at 130° C. The continuous-flow setup was constructed from astainless steel tubing (500 μm internal diameter) wrapped in coils. Thereactor effluent was next conveyed to a second reaction coil operated at180° C. The second reaction coil was constructed from stainless steeltubing (500 μm internal diameter) wrapped in coils (2.5 mL internalvolume, corresponding to a total residence time of 15 min). Aback-pressure regulator set at 500 psi was inserted downstream. Thecrude effluent was collected and analyzed. It contained 63% of compound1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa), 7% ofrac-ketamine and 30% of unreacted(2-chlorophenyl)(1-hydroxycyclopentyl)methanone (IIIa).

This example highlights the superiority of flow versus batch because ofits possibility to successfully telescoping two reaction steps into one.

Example 21: Preparation of(R,S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride,((R,S)-ketamine hydrochloride, rac-1·HCl) in Batch in Ethanol

A solution of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa)in absolute ethanol (0.42 M) was heated at 170° C. under microwaveirradiation in a 20 mL batch vial for 15 min under 20 bar of pressure(Table 2) in the presence of a fourth additive in the form of ahomogeneous acid catalyst (HCl in ethanol 1M). The reaction mixture wasevaporated, affording (R,S)-ketamine hydrochloride, rac-1·HCl in 54%conversion and 50% selectivity.

Example 22: Preparation of(R,S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride,(R,S)-ketamine hydrochloride, rac-1.HCl) in Batch in o-dichlorobenzene

A solution of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa)(2.00 g, 8.41 mmol, 1 eq.) was dissolved in 20 mL of o-dichlorobenzenein the presence of 2.11 mL (8.44 mmol, 2 eq.) of dioxane solution ofhydrochloric acid, and the resulting mixture was refluxed for 30 min ina round-bottom flask equipped with a condenser. The mixture was allowedto cool down to room temperature, and a white precipitate was collected.The solid was filtrated and washed with 50 mL of diethyl ether.(R,S)-ketamine hydrochloride (rac-1·HCl) was obtained with 74% yield(>99% selectivity). Characterization ¹H NMR (400 MHz, D₂O) 7.86-7.73 (m,1H), 7.52 (d, J=5.9 Hz, 3H), 3.36-3.15 (m, 1H), 2.46 (dd, J=11.7, 6.1Hz, 2H), 2.33 (s, 3H), 2.01 (dt, J=16.5, 3.8 Hz, 1H), 1.90-1.74, (m,2H), 1.64 (dtt, J=16.4, 13.1, 4.3 Hz, 2H). ¹³C NMR (100.6 MHz, D₂O)211.1, 132.8, 132.0, 131.8, 72.6, 39.5, 36.2, 30.1, 27.1, 21.2.ESI-HRMS: [M+H]⁺ calcd: 238.09932, found: 238.09946.

Example 23: Preparation of(R,S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride,(R,S)-ketamine hydrochloride, rac-1.HCl) in Flow

A solution of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol (IVa)in absolute ethanol (0.36 M) was pumped at a flow rate of 0.24 mL min⁻¹with a HPLC pump, and a solution of a fourth additive in the form of apharmaceutically acceptable acid which is HCl in absolute ethanol (0.9M) was pumped at a flow rate of 0.16 mL min⁻¹ with a metal-free HPLCpump. Both streams were mixed through a static PEEK T-mixer, and nextreacted in a microfluidic reactor loop constructed from a PFA capillaryembed in a copper coil (2 mL internal volume, corresponding to aresidence time of 5 min). The reactor was operated at 175° C. under 250psi of counter-pressure. The reactor effluent was collected andprocessed, affording (R,S)-ketamine hydrochloride (rac-1·HCl) in 70%yield (>99% purity, HPLC). This example shows the superior effect ofthis reaction step in flow versus this reaction step in batch (cfrexamples 21 and 22) with an increase in the purity of the productobtained.

What is claimed is:
 1. A method for synthesizing a compound of formula

wherein each R independently represents an optionally substituted aryl,heteroaryl, alkyl, perfluoroalkyl, cycloalkyl, alkoxy, aryloxy, acyl,carboxyl, hydroxyl, halogen, amino, nitro, cyano, sulfo or sulfhydrylgroup, in ortho, meta or para position to the cycloalkylamine moiety; R¹and R² each independently represents a hydrogen atom, a lower alkylgroup or a cycloalkyl group; R³ represents a hydrogen group, substitutedaryl, heteroaryl, alkyl, perfluoroalkyl, cycloalkyl, alkoxy, aryloxygroup; Y represents an oxygen atom, a sulfur atom, a NH group, a NR⁴group or a CH₂ group; R⁴ represents a hydrogen atom or an alkyl, aryl ora heteroaryl group; n and m each independently represents an integerfrom 1 to 5; or a pharmaceutically acceptable salt thereof; or aprecursor thereof; wherein the method comprises step (a) of reacting acompound of formula (II)

wherein R, R³, Y, n and m are as defined above in relation to thecompound of formula (I) with an oxygenating agent, a first additive, anda second additive in a solvent in a fluidic network under thermal and/orphotochemical conditions to form a compound of formula (III)

wherein R, R³, Y, n and m are as defined above in relation to thecompound of formula (I); and optionally step (b) of reacting a compoundof formula (III) with a nitrogen containing nucleophile in the presenceof a third additive and/or a solvent in the fluidic network or in abatch process under thermal conditions to form a compound of formula(IV)

wherein R, R₁, R₂, R₃, Y, n and m are as defined above in relation tothe compound of formula (I); and optionally (c) reacting a compound offormula (IV) in a fluidic network, optionally in the presence of afourth additive, under thermal conditions to form a compound of formula(I); wherein a fluidic network comprises one or more micro- and/ormeso-channels having an internal dimension of from 100 μm to 2000 μm;wherein a lower alkyl group is a saturated optionally substitutedstraight- or branched-chain hydrocarbon containing from 1 to 4 carbonatoms; wherein the oxygenating agent is gaseous dioxygen, a solventsaturated in dioxygen, air, or a peroxide.
 2. The method as defined inclaim 1 wherein the fluidic network comprises transparent micro- and/ormeso-channels where step (a) is carried out under photochemicalconditions.
 3. The method as defined in claim 1 wherein one or more ofthe steps comprises one or more of the following steps: (i) flowing afluid sample into a micro-/meso-channel; and/or (ii) performing anin-line purification; and/or (iii) performing an in-line analysis;and/or (iv) performing a chemical reaction in the micro-/meso-channel.4. The method as defined in claim 1 wherein step (a) comprises reactinga compound of formula (II) with an oxygenating agent, a first additiveand a second additive which is a base in a solvent under thermalconditions to form a compound of formula (III).
 5. The method as definedin claim 1 wherein step (a) comprises reacting a compound of formula(II) with an oxygenating agent, a first additive and a second additivewhich is a catalyst in a solvent in a fluidic network underphotochemical conditions to form a compound of formula (III).
 6. Themethod as defined in claim 1 wherein step (a) is telescoped to step (b).7. The method as defined in claim 1 wherein steps (a), (b), and (c) arecarried out in a fluidic network that comprises micro- and/ormeso-channels.
 8. The method as defined in claim 1 wherein step (c)comprises flowing a fluid sample comprising a compound of formula (IV)into a micro-/meso-channel; and/or performing an in-line purification ofthe compound of formula (IV); and/or performing an in-line analysis ofthe compound of formula (IV); and/or performing a chemical reaction, inthe micro-/meso-channel, to convert the compound of formula (IV) to thecompound of formula (I).
 9. The method as defined in claim 1 whereinstep (b) further comprises a dehydration reagent.
 10. The method asdefined in claim 1 wherein step (b) is carried out at a temperature from60° C. to 180° C.
 11. The method as defined in claim 1 wherein step (b)is telescoped to step (c).
 12. The method as defined in claim 1 whereinstep (c) comprises a fourth additive which is an acid.
 13. The method asdefined in claim 1 wherein step (c) is carried out at a temperature offrom 160° C. to 260° C.
 14. The method as defined in claim 1 whereinstep (c) is telescoped to a subsequent process operation.
 15. The methodas defined in claim 1 wherein step (c) is telescoped to a subsequentchemical transformation.
 16. The method as defined in claim 1 whereinstep (c) reacting the compound of formula (IV) in a solvent which is analcohol in which the solubility of a pharmaceutically acceptable salt ofa compound of formula (I) can be altered either by cooling or by addingan antisolvent.
 17. The method as defined in claim 6 wherein step (a)additionally comprises a step of an in- or off-line downstreampurification including quench, liquid-liquid extraction, liquid-liquidseparation, gas-liquid separation, filtration on silica gel or in-linecrystallization.
 18. The method as defined in claim 11 wherein step (b)additionally comprises a step of an in- or off-line downstreampurification including quench, liquid-liquid extraction, liquid-liquidseparation, or gas-liquid separation.
 19. The method as defined in claim1 wherein the peroxide is hydrogen peroxide.